The preparation of carbamazepine of formula III from iminostilbene or 5H-dibenz[b,f]azepine ("iminostilbene") of formula I ##STR4## was described for the first time by W. Schindler in e.g. German accepted patent application No. 1,136,707, and in Swiss patent No. 54,023.
According to this method, the iminostilbene is suspended in toluene. Phosgene is introduced into this suspension, and the reaction mixture heats up to 70.degree. C. Then, the reaction mixture is refluxed during the further addition of phosgene and is kept at boiling until the iminostilbene completely reacted and the evolution of hydrogen chloride has ceased. The introduction of phosgene is discontinued as soon as the reaction solution is free of iminostilbene. Excess phosgene is removed from the reaction mixture with dry nitrogen, or dry air, such as is described in German accepted patent application No. 1,001,271, in which the excess phosgene is blown out with dry air at the end of the phosgenation of 5H-10,11-dihydro-dibenz[b,f]azepine or iminodibenzyl. The so detoxified reaction solution is worked up conventionally and the resulting 5-chlorocarbonyl-5H-dibenz[b,f]azepine ("CCDA") of formula II ##STR5## is recovered by crystallization, and is aminated in a known manner to the carbamazepine end product of formula III.
The known methods of preparation are all carried out in an inert, anhydrous solvent at temperatures above 100.degree. C., such as in toluene, chlorobenzene, or o-dichlorobenzene (see, for example, the various publications summarized by B. Renfroe, et al. in Heterocyclic Compounds, Vol. 43, Azepines, part I, John Wiley & Sons Publisher, New York, 1984, page 524, table 118).
The dissociation of the iminostilbene hydrochloride formed by the phosgenation, into hydrogen chloride gas and free iminostilbene is carried out in all industrial processes by heating the reaction mixture to the boiling point in the neutral solvent and passing in phosgene under reflux conditions.
All high temperature phosgenations, carried out in the prior art, are conducted at 100.degree. C. and higher, to achieve a complete phosgenation of the iminostilbene, or of the iminodibenzyl.
The known processes for preparing carbamic acid chlorides from secondary amines are summarized in a table in the organic chemistry methodology manual of Houben-Weyl (vol. E 4, pages 46-50, Georg Thieme Verlag, Stutgart, New York City, Publisher, 1983). In these processes most often aromatic hydrocarbons, such as benzene, toluene or chlorobenzene, are used as solvents.
If the synthesis is carried out at low temperatures, when the phosgene is passed into a solution of the secondary amine, only half of the amine is converted into the desired carbamic acid chloride because the hydrogen chloride released during the reaction converts the other half of the amine into the hydrochloride. The amine hydrochloride precipitates in crystalline form. Thus, the yield of carbamic acid chloride can even in the most favorable cases amount only to 50%.
Since the work of H. Erdmann, et al. (J. Prakt. Chem. (2), Vol. 56, 7, 1897), it is known that the conversion can be completed if an inert, anhydrous base, such as pyridine, is used in an at least equimolar amount.
According to the Houben-Weyl manual (see above), in addition to pyridine, also triethylamine and, of course, the amine itself that is to be reacted, are suitable as inert bases. The cold phosgenation becomes more costly, since at least equimolar amounts of the inert base are always required. The process is costly and is more cumbersome, because the amine hydrochloride has to be separated out for recovering the inert base. Therefore, the cold phosgenation in the presence of inert auxiliary bases is important only for the reaction of temperature sensitive secondary amines, which increasingly tend to undergo side reactions at the high temperatures of the hot phosgenation.
In industry, the reaction is suitably carried out at temperatures above 100.degree. C. The Houben-Weyl manual states in this connection that "[A]dvantageously, the reaction mixture is heated to a temperature above 100.degree. C. while further phosgene is introduced, and the entire amine chloride is converted into the carbamic acid chloride."
The hydrogen chloride gas released by this thermal dissociation, carries along appreciable amounts of phosgene. Therefore, the off-gas must be detoxified and destroyed in special off-gas apparatus. Such a procedure can seriously endanger the environment in the case of an accident, because of the danger presented by the extremely toxic nature of phosgene which is a gas under ambient conditions.
The procedure of hot phosgenation has, above all, the following serious disadvantages:
the burden of having to deal with large amounts of liberated hydrogen chloride off-gas including phosgene and the entrained solvent vapors, and the resulting environmental protection problems; PA1 long reaction times of more than 18-24 hours in contact with highly corrosive media; PA1 large expenditure of energy; PA1 a number of side reactions and the dark coloration of the reaction product, which leads to a substantial decrease in the quality of the carbamazepine end product; and PA1 increasing formation of unwanted 9-methylacridine byproduct at temperatures above 90.degree. C. which represents a contraction of the 7-membered ring of the iminostilbene.
Only at temperatures of from about 90.degree. C. does the thermal dissociation of the iminostilbene hydrochloride into free iminostilbene and hydrogen chloride gas proceed sufficiently rapidly to achieve reaction times which are acceptable for industrial purposes. However, iminostilbene is a temperature sensitive amine. Therefore, iminostilbene is suitably phosgenated by the method of Schindler, described in the aforementioned German accepted patent application No. 1,136,707.
The process variant preferred by Schindler is dividing the phosgenation into two stages, a cold phosgenation stage resulting in an about 50% conversion in the first phase, and a hot phosgenating stage. Conversion carried out in a second stage has clear advantages over a direct single stage hot phosgenation, because the yields are appreciably increased in this manner, the side reactions that take place above 90.degree. C. are suppressed, and the quality and color of the end product are improved. Nevertheless, the aforementioned disadvantages continue to exist in the second stage of the reaction, i.e. from the start of the heating to 90.degree. C. and during the thermal dissociation of the iminostilbene hydrochloride until the end of the reaction.
An excess of phosgene is introduced into the reaction mixture to utilize the gentle reaction conditions of the first, the cold phosgenating stage as much as possible. A pressure surge can occur if the reaction mixture is heated subsequently to dissociate thermally the iminostilbene hydrochloride. This dangerous possibility is also mentioned in the Houben-Weyl manual (volume E 4, page 744).
When a pressure surge occurs, the spontaneously released hydrogen chloride gas also carries along appreciable amounts of phosgene. Therefore, the apparatus for destroying or detoxifying the off-gases must be sufficiently large to avoid the release of phosgene into the atmosphere.
The reaction is advisably carried out at temperatures of between 90.degree. C. and 100.degree. C. to suppress the unwanted side reactions and the formation of the methylacridine byproduct. The phosgenation proceeds sufficiently rapidly at this temperature. However, the partial pressure of the phosgene is appreciably increased at the higher temperature, compared to that of the cold phosgenation, therefore it is not possible to prevent the steady escape of large quantities of phosgene being carried along by the liberated hydrogen chloride. This can, of course, be also realized from the fact that appreciably less time is required for the conversion of the first half of the iminostilbene in the cold phosgenation stage, than for the conversion of the second half in the hot phosgenation stage.
The reaction solution has to be detoxified after the complete conversion of the iminostilbene. The excess phosgene is blown out of the reaction solution with dry nitrogen as a rule, or a portion of the solvent is distilled off until the reaction mixture is free of phosgene. This detoxification method has the disadvantage that phosgene can leak into the atmosphere if there are any leaks due to the high gas pressure in the apparatus. Therefore, in the long run there is a constant danger of atmospheric contamination by the escaping phosgene.
In addition to the method of directly phosgenating iminostilbene of formula I, other methods of preparing carbamazepine of formula III are known. These start out from 10,11-dihydro-5H-dibenz[b,f]azepine ("iminodibenzyl") of formula IV ##STR6## In this connection see British patent No. 1,246,606 and East German patents Nos. 82,719; 100,948; 101,671; 102,149; 102,150; 102,151; 108,535; 133,052; 234,862 A1; and 234,863 A1. According to the methods described in these references, iminodibenzyl is reacted with phosgene in a boiling, inert, aromatic solvent, preferably toluene, or chlorobenzene. Phosgene is introduced into the refluxing material. Thus these methods also employ hot phosgenation with all of its attendant disadvantages.
The resulting 5-chlorocarbonyl-5H-10,11-dihydro-dibenz[b,f]-azepine of formula V ##STR7## is reacted in an inert organic solvent with elemental bromine, or is otherwise subjected to selective bromination and the corresponding 10-monobromo derivative formula VI ##STR8## and/or the 10,11-dibromo-derivative formula VII ##STR9## is formed.
The bromo compounds of formulae VI and/or VII are subsequently dehydrobrominated and/or are thermally debrominated. A partial exchange (30-40%) of the chlorine atom of the 5-chlorocarbonyl group for a bromine atom takes place during such a thermal process. Due to the required high reaction temperatures (150.degree. C.-170.degree. C.) and because of the liberated bromine, these drastic reaction conditions necessarily lead to uncontrollable side reactions, such as bromination of the ring, resinification, cracking, and discoloration.
Thus the CCDA prepared by these processes contains, in addition to numerous, particularly bromine-containing, byproducts also some greasy, tarry, colored contaminants, the removal of which requires an undue effort.
The nature and structure of these byproducts is not known. The customary purification methods lead to appreciable losses.
No purification method was known until now, which can economically solve the problem of the residual bromine content. Thus, as determinedly high pressure liquid chromatography, the CCDA so prepared is present the average in an amount of 90%, and the precursor for the carbamazepine end product, contains about 10% impurities.
The CCDA intermediate prepared by the aforementioned methods can be recovered either by treating the hot solution with activated charcoal, filtering and isolating the product after crystallization or, after filtration, distilling off the solvent, and letting the melt of the product run into a precipitation bath of a different, suitable solvent, and then removing the crystallized product.
The so recovered CCDA intermediate is next aminated in a suitable solvent. Ammonia gas, liquid ammonia, concentrated aqueous ammonia, or ammonium salts in an aqueous solution can be used for the amination. The following amination methods are described in the literature.
According to the methods of the East German patents Nos. 82,719 and 102,150, Swiss patent No. 366,541, and German accepted patent application No. 1,001,271, the CCDA is partially or completely dissolved in ethanol or methanol. The resulting suspension or solution is treated with gaseous ammonia at temperatures, which are higher than the boiling point of the alcohol solvent, that is, the amination reaction is carried out under pressure in an autoclave. This is a technically manageable process, but a difficulty is presented by the fact that the alcohols are not inert, but react to an undesirable degree with the CCDA in a side reaction which cannot be suppressed. The corresponding esters are formed as byproducts of that undesired side reaction.
During the amination in methanol, regardless of whether the reaction is carried out under anhydrous conditions with gaseous ammonia, or with a concentrated aqueous solution of ammonia, about 1%-2% of a 5-carbomethoxy-5H-dibenz[b,f]-azepine byproduct is formed. This ester is not readily removed during the subsequent recrystallization of the crude carbamazepine end product. Even after two recrystallizations, the end product still contains about 0.1% of the 5-carbomethoxy-5H-dibenz[b,f]-azepine byproduct. Since according to the European Pharmacopoeia 2nd Ed., 1987, Part II, Fasc. 11, p. 543, Maisonneuve S.A. Publ., Saint-Ruffeine, France, the concentration of any single impurity may not exceed 0.01%, all amination methods in alcoholic solvents especially in primary, low molecular weight alcohol solvents lead to a carbamazepine, which does not meet the quality requirements. Therefore, these amination methods cannot be employed because they fail to satisfy the applicable quality requirements.
According to the method of East German patent No. 82,719, the amination can also be carried out in an inert aromatic solvent, (see Example 1, amination of 33.7 g of 5-chlorocarbonyl-10-bromo-iminodibenzyl in 500 ml benzene in an autoclave). This process variant has the advantage that esters cannot be formed, however, since the carbamazepine end product is formed is a polar compound, it is not readily soluble in benzene or toluene, even at elevated temperatures. Therefore, considerably more solvent is required to enable the stirring and mixing necessary for carrying out the indispensably quantitative conversion of the carbamic acid chloride. This results in the case of this process variant in a drastic drop in the yield for a given reactor size and reaction time.
According to the method of East German patent No. 264,115 A 3, the amination is also carried out in aromatic solvents, in that the solution of the 5-halocarbonyl-5H-dibenz[b,f]azepine is run into the aminating agent. A 15% to 25% aqueous solution of ammonia or aqueous ammonia, salt solution is used as aminating agent. Nonionic surfactants, or quaternary aryl-alkyl-ammonium salts are used as surface active materials, to enable working in a concentrated form. These materials are intended to insure better mixing and stirrability for achieving a quantitative conversion. Suitably, halogenated aromatic hydrocarbons, such as chlorobenzene, or bromobenzene, are used. It is noted that the trend is clearly towards methods that do not employ chlorinated hydrocarbons, to avoid contamination of the efficient and for more environmentally friendly operations.
All attempts failed to convert the method described in East German patent No. 264,115 A 3 with toluene as solvent, to a large scale, industrial production method. Benzene was not even considered for use as a solvent, because of its toxic tendency to product leukemia. After at most 1 hour in a conventional 3,200 liter vessel with an impeller stirrer run at 103 rpm, or with an anchor type stirrer, as the reactions proceeded, the reaction mixture could no longer be stirred. The reaction came to a halt long before the required complete conversion, because the precipitated carbamazepine rises to the top and forms an approximately 1 m thick, strongly coherent "crystalline cake", which can no longer be dispersed by stirring. The mass can be made stirrable within 1 to 2 hours by raising the temperature to about 105.degree. C. to 110.degree. C. under an increasing pressure in a closed system. However, as a consequence of the increase in temperature, the unreacted CCDA that is still present decomposes by hydrolysis. In this manner, up to 8% of the 5-chlorocarbonyl-iminostilbene reverts to the golden yellow starting material iminostilbene, and the carbamazepine end product becomes discolored. Purification is expensive and considerably increases the cost of production.
For the same reasons, it was also not possible successfully to convert to industrial scale production the method, proposed in East German patent application No. WP C07D/320613.5 (which is based on the method of East German patent application No. WP C07D/320612.7).
The amination process of East German patent No. 126,329 is the presently known and used method. According to this method, the isolated CCDA intermediate is introduced into butyl acetate and aminated with concentrated aqueous ammonia. Although this reaction takes place in a 2-phase system, the decomposition by hydrolysis of CCDA can also not be completely avoided in this case. A certain reverse reaction to the iminostilbene starting material, the extent of which varies with the reaction parameters selected, is always observed to take place.
Therefore, a need exists for a continuous, low cost, industrially upscalable method for preparing carbamazepine which meets the purity requirements of the European Pharmacopoeia.